Correlation between 5-HT7 receptor affinity and protection against sound-induced seizures in DBA/2J mice.
Audiogenic seizures can be induced in DBA/2J mice following intense auditory stimulation. A number of neurotransmitters, including 5-hydroxytryptamine (5-HT), are believed to be involved in mediating this effect since it has been shown previously that depletion of 5-HT or blockade of 5-HT receptors protects DBA/2J mice from these audiogenic seizures. The present study was undertaken to determine whether antagonism of the newly identified 5-HT7 receptor may protect DBA/2J mice from audiogenic seizures by attempting to correlate in vivo potency of compounds with their affinity at the 5-HT7 receptor. All compounds used in the correlation were shown to be antagonists at the 5-HT7 receptor and a statistically significant correlation was observed between 5-HT7 affinity and doses for half-maximal response (ED50) for protection of DBA/2J mice from sound-induced seizures (r = 0.80; P < 0.05). No significant correlation was observed between in vivo activity and affinity at either 5-HT1A, 5-HT2A or 5-HT2C receptors. It is also unlikely that interactions between the 5-ht5 receptor will protect DBA/2J mice from audiogenic seizures since metergoline and mesulergine which are both active in this in vivo model have no affinity for the 5-ht5 receptor. There are similarities between the pharmacology of the 5-HT7 receptor and that of the 5-HT1A receptor, however the correlation between the in vivo potency in DBA/2J mice and 5-HT1A affinity was not significant. Furthermore, the 5-HT1A receptor antagonist WAY 100135 did not protect DBA/2J mice from audiogenic seizures at doses that antagonise 5-HT1A receptor-mediated effects in mice. These data suggest that antagonism of 5-HT7 receptors may protect against audiogenic seizures in DBA/2J mice although a definitive conclusion must await studies with selective 5-HT7 antagonists.
Bourson
A
A
Pharma Division, Preclinical Research, F. Hoffmann-La Roche, Basel, Switzerland.
Kapps
V
V
Zwingelstein
C
C
Rudler
A
A
Boess
F G
FG
Sleight
A J
AJ
D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000627:therapeutic use*; D016466:CHO Cells; D006224:Cricetinae; D004873:Ergolines / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D008784:Methysergide / Q000378:metabolism / Q000627:therapeutic use; D008803:Mianserin / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D008811:Mice, Inbred DBA; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012640:Seizures / Q000209:etiology / Q000517:prevention & control*; D012702:Serotonin Antagonists / Q000378:metabolism / Q000627:therapeutic use*
D000927:Anticonvulsants; D004873:Ergolines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor; D008803:Mianserin; C031649:mesulergine; D008784:Methysergide